Project Summary: Natural Killer (NK) cells are lymphocytes of the innate immune system. NK cells defend us by inducing antibody-dependent cell mediated cytotoxicity (ADCC) where NK cells lyse antibody coated virally- infected target cells. Recent experiments showed generation of long-lived ?memory-like? NK cells, similar to memory lymphocytes in the adaptive immune system, in mouse and humans challenged by viral infections (such as cytomegalovirus). These memory NK cells generated a more vigorous ADCC response compared to their nave counterparts which make the memory NK cells an attractive candidate for augmenting monoclonal antibody based immunotherapies against cancer and infectious disease. However, two major issues limit the use of ?memory-like? NK cells for such therapies: 1) A rudimentary understanding of mechanisms underlying NK cell-mediated ADCC is lacking; and 2) humans and mice show key differences in the NK cell signaling networks, which regulate ADCC. We address the above challenges by developing computational models with predictive powers for antibody responses induced by NK cell subsets (from nave to memory) in humans and mice by synergistically combining data-driven and mechanistic in silico models (rooted in statistical physics, nonlinear dynamics, information theory, statistics, and chemical engineering) with single cell mass cytometry by time of flight (CyTOF) and state-of-the-art wet lab experiments in primary NK cells obtained from human subjects and genetically modified mice. The objective of the proposal is to quantitatively characterize mechanisms underlying ADCC in diverse NK cell subsets in humans and mice and then use this quantitative understanding to develop novel mouse models of ADCC that reflect the situation in humans more accurately. We will pursue two aims: Aim 1: Modeling ADCC activity in human nave and memory NK cell subsets. Aim 2: Modeling ADCC in mouse NK cells. The expected outcome of quantitative characterization of the differences and synergies in mechanisms of ADCC induced by CD16 and CD32 receptors in different NK cell subsets (nave to memory primary NK cells) (Aim 1) will help us generate improved mouse models that more accurately represent ADCC mediated by human NK cells (Aim 2). This unique framework will provide the scientific community with a mouse model for ADCC that more accurately reflects the situation in humans, a critical asset for pre-clinical development of monoclonal antibody therapeutics for cancer and infectious diseases.